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Benzimidazole retinoic acid receptor-related orphan receptor modulators and uses thereof

Inactive Publication Date: 2016-01-28
INNOV17
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about certain compounds that can be used to treat diseases and disorders that are influenced by a protein called ROR. These compounds can be used alone or in combination with other drugs to provide more effective treatment options for patients with ROR-related diseases.

Problems solved by technology

Also, in several autoimmune disease models, there is a relative imbalance of increased pathologic TH17 cells over low numbers of protective immunosuppressive CD4+CD25+Foxp3+ regulatory T cells [TReg] (Edwards et al.

Method used

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  • Benzimidazole retinoic acid receptor-related orphan receptor modulators and uses thereof
  • Benzimidazole retinoic acid receptor-related orphan receptor modulators and uses thereof
  • Benzimidazole retinoic acid receptor-related orphan receptor modulators and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of phenyl(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)piperidin-1-yl)methanone

[0301]

[0302]To a stirred solution of 1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazole (0.200 g, 0.54 mmol, 1.0 eq) in dichloromethane (5 mL), benzoyl chloride (0.101 g, 0.65 mmol, 1.2 eq) was added at 0° C. followed by triethylamine (0.163 g, 1.62 mmol, 3.0 eq) and the mixture was stirred room temperature for 1 h. After completion of the reaction (monitored by TLC, 20% ethyl acetate in hexanes Rf=0.55), water (10 mL) was added to the reaction mixture and it was extracted with dichloromethane (10 mL). The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography on silica gel, 100-200 mesh, eluting with 10% ethyl acetate in hexanes to afford phenyl(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-...

examples 2-4

[0303]The above experimental protocol was used for synthesis of the compounds shown in the table below:

YieldExampleIntermediateg, (%)LCMS20.12  (80)Purity: 59.18% (ES+) m / z 484.50; tr = 1.56 min. 2-Phenyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)piperidin-1-yl)ethanone30.06  (41)Purity: 88.55% (ES+) m / z 498.28; tr = 1.59 min. 3-Phenyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)piperidin-1-yl)propan-1-one40.077 (52)Purity: 90.53% (ES+) m / z 490.33 (M + H+); tr = 1.71 min. 2-Cyclohexyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)piperidin-1-yl)ethanone

example 5

Synthesis of 1-((1-(phenylsulfonyl)piperidin-4-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazole

[0304]

[0305]1-((1-(Phenylsulfonyl)piperidin-4-yl)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazole was prepared from 1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazole and benzene sulfonyl chloride using the procedure described in Example 1 to give a 27% yield of product. Purity: 60.80%; (ES+) m / z 506.16 (M+H−); tr=1.65 min.

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Abstract

Provided herein are compounds of the formulas (I) and (II):as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of Retinoic Acid Receptor-Related Orphan Receptor regulated diseases and disorders.

Description

FIELD OF THE INVENTION[0001]The invention relates to Retinoic Acid Receptor-Related Orphan Receptor (ROR) regulated diseases and disorders. More particularly, the invention relates to ROR modulators; compositions comprising a therapeutically effective amount of a ROR modulator; and methods for treating or preventing ROR regulated diseases and disorders. All documents cited to or relied upon below are expressly incorporated herein by reference in their entirety.BACKGROUND OF THE INVENTION[0002]There are high unmet medical needs in the few established therapies for several autoimmune, inflammatory, metabolic and oncologic diseases. Despite the diverse clinical manifestations of these diseases, Retinoic Acid Receptor-Related Orphan Receptors (RORs) regulate and contribute to the pathogenesis of these diseases through modulation of immune responses and lipid / glucose homeostasis. Only recently has the critical regulatory role of RORs been well-characterized and target validated in severa...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D403/14C07D487/08
CPCC07D401/14C07D487/08C07D403/14A61P1/00A61P11/00A61P17/06A61P29/00
Inventor GAWECO, ANDERSONTILLEY, JEFFERSONBLINN, JAMES
Owner INNOV17
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